Neuroblastoma a tough nut to crack ?

Neuroblastoma:
A Tough Nut to
Crack ?
Mustafa Mohamed Selim
NCI, Cairo University
0

“Education should not prepare you for the
world as it is, but inspire you to change
the world in what it should be”
(Amrani)

What
How
Why
they do?
Exist
Belief
Purpose
Get up in the
morning
Inspired
organization
Idea was adapted from SimonSinek talk (how great leaders inspire actions)
Non inspired
organization

 Neuroblastoma (NB) is one of the embryonal
malignancy.
 NB is one of the most common solid tumors of
early childhood.
 It occupying ~8% of pediatric malignancies.
Introduction
Nakagawara A. COG and JCCG. Jpn J Pediatr Hematol Oncol
2015;52:359–64. (in Japanese)

Neuroblastic tumors includes:
• Neuroblastoma,
• Ganglioneuroblastoma and
• Ganglioneuroma.
Clinical behavior range from:
• Spontaneous regression,
• Maturation to a benign ganglioneuroma, or
• Aggressive disease with metastatic dissemination
leading to death.
(Brodeur et al., 2011)
Neuroblastic tumours ??

Epidemioloy
• The most common cancer in infants “<1 year old”
• The most common extra-cranial solid cancer in childhood
• 90% of cases are diagnosed by age 5 years.
• Very rare in people over the age of 10 years.
• The average age (18 months)→diagnosis “Sporadic”.
• The average age (9 months)→diagnosis “Familial”.
• It accounts for about 8% of all cancers in children.
• It accounts for around 15% of all pediatric oncology deaths.
• > 50 % of patients with NB have metastatic disease at the time of diagnosis.
Key statistics
More commen in males & white children,
but in females with Turner syndrome

 African genomic ancestry has also been shown to be
significantly associated with high-risk neuroblastoma,
supporting a genetic etiology for the racial disparities
in survival observed in neuroblastoma.
Gamazon ER, Pinto N, Konkashbaev A, et al: Trans-population analysis of genetic
mechanisms of ethnic disparities in neuroblastoma survival. J Natl Cancer Inst
105:302-309, 2013

Key words
The capacity to undergo regression1
The capacity to undergo maturation2
A superior prognosis for infants3

Key features of Neuroblastoma
NEUROBLASTOMA
 The capacity to undergo regression→ LR (IVs)
• No MYCNamplification
• Near triploid nmber of chromosomes.
• No loss of chromosome 1p.
{Ambros et al., 2000

NEUROBLASTOMA
 The capacity to undergo maturation → IR (Residual after
surgery)
 A superior prognosis for infants → < 18 vs >18 MPersisting residual and maturing tumors in IR patients
with Neuroblastoma were not associated with tumor
progression, despite MIBG uptake and/or elevated
catecholamines {Marachelian et al., 2012}.

NEUROBLASTOMA
 The capacity to undergo maturation → IR (Residual after
surgery)
 A superior prognosis for infants → < 18 vs >18 M
Holly J. et al., Pediatric Blood Cancer

Tumors of neural crest
Phechromocytoma
Carcinoid
Medullary cancer
of thyroid
Neurofibromatosis
Neuroblastoma
EMBRYOGENSIS

History & examination
Suspicion
TO REACH DIAGNOSIS

 C/P; subutenous nodules, massive hepatomegally, bone
marrow involvment, adrenal hemorrhage, and hydrops fetalis.
 Diagnosis; prenatal (US) * post-natal (biopsy).
 Treatment;
 Most of cases undergo spontaneous regression.
 If symptomatic (RD)→ low dose chemotherapy.
 If chemotherapy failed (emergency RD)→ 150-200 cGy.
Neonatal Neuroblastoma

 Origin; from olfactory neuroepithelium.
 Behaviour; varient (indolent vs agressive).
 Age; peak 3rd & 6th decade.
 Treatment; surgery + radioterapy +/- adjuvent
chemoterapy.
Olfactory Neuroblastoma

 Incidence:1-2% of NB diagnoses
 Anaplastic lymphoma kinase (ALK) germline mutation
 PHOX2B germline mutation
• Neurocristopathy syndrome: Central
hypoventilation, Hirshprung’s, NBL
Familial Neuroblastoma
Germline

Diagnostic evaluation
Suspicion
TO REACH DIAGNOSIS

• Catecholamine biosynthetic enzymes
were stained in primary tumors from
patients with neuroblastoma.
• Score per staining
 Catecholamine biosynthetic enzymes
 TH→ tyrosine hydroxylase,
 DDC→ dopa decarboxylase,
 DBH→ dopamine b-hydroxylase.

Staging & risk stratification
Diagnostic evaluation
Suspicion
TO REACH DIAGNOSIS

Advances in Risk Classification for
Neuroblastoma

1971
Development of Evans
staging system.
1984
Development of
Shimada system
1986
Development
of INSS criteria.
1997
Identification that 17 q gain
is associated with poor
prognosis.
Neuroblastoma Staging history
2005
• Meeting of INRG to develop
INRG Staging System and
Risk Classification Criteria.
• Identification that loss of 1p
and 11q is associated with
poor prognosis.
1999
Development of INPC

Based on the assessment of resectability and surgical examination of lymph node
involvement
INSS

Description of International Neuroblastoma Response Criteria
•Complete Remission (CR): No tumor, no metastases, normal markers.
•Very good Partial Remission (VGPR):
Primary; reduction more than 90%, but less 100%
Metastases; no tumor except bone {all preexisting lesions improved}
Markers; decreased more than 90%
•Partial Remission (PR):
Primary; reduction 50%-90%
Metastases; no new lesions; 50%-90% reduction in measurable sites; 0-1
BM samples positive; bone lesions the same as VGPR.
Markers; decreased 50%-100%
•Mixed Response (MR):No new lesions; more than 50% reduction of any
measurable lesion {primary or metastases} with less than 50% reduction in any
other; less than 25% increase in any existing lesion.
•No Response (NR): No new lesions; less than 50% reduction but less than 25%
increase in any existing lesion.
•Progressive Disease (PD): Any new lesion; increase of any measurable lesion by
more than 25%; previous negative marrow positive for tumor.

01 02 03
Age
01
Disease stage
02
Tumor biologic features
03
to assign patients to appropriate therapy based on risk of disease recurrence.
Current risk classification utilize

01
Age
01
London,W.B., et al. Evidence for an age cutoff greater than 365 days for neuroblastoma risk group stratification in the Children’s Oncology Group. J.
Clin. Oncol. 2005, 23, 6459–6465. [CrossRef] [PubMed]
In the more recent era, international cooperative group
analyses have provided evidence to support an increase
to 18 months of age at diagnosis as an appropriate
cutoff for separating younger from older patients with
respect to risk stratification.

•COG uses age, MYCN status, stage, histology, and DNA ploidy.
•SIOPEN uses age, MYCNstatus, and surgical risk factors defined
by imaging for assigning risk - group for locoregional tumors.
Prognostic factors
• Stage.
• Age ( < 18 months versus ≥ 18 months (547 days)).
• Histological category (ganglioneuroma, ganglioneuroblastoma– intermixed).
• Grade of tumor differentiation (differentiating versus undifferentiated or
poorly differentiated).
• MYCN status.
• Presence/absence of 11q aberration.
• Ploidy ( ≤ 1.0 versus > 1.0).
COG Risk Stratification

01 02
Age
01
Disease stage
02
INRGSS has replaced the INSS

INRGSS
• The International Neuroblastoma Risk Group (INRG) classification system
was based on analyses of data collected on more than 8,800 patients
diagnosed between 1990 and 2002 in North American, Europe, Japan, and
Australia.
• The system uses combinations of seven prognostic risk factors to define 16
pretreatment groups stratified by these prognostic markers.
• Based on the 5-year EFS rates of the 16 pretreatment groups they were
categorized to a very low, low, intermediate, or high-risk group.Cohn SL, Pearson AD, London WB, et al: The International Neuroblastoma Risk Group (INRG) classification
system: An INRG Task Force report. J Clin Oncol 27:289-297, 2009

INRGSS
Cohn SL, Pearson AD, London WB, et al: The International Neuroblastoma Risk Group (INRG) classification
system: An INRG Task Force report. J Clin Oncol 27:289-297, 2009

INRGSS
•Pre- treatment clinical staging stystem
•It was designed for INGSS
2009
T. Monclair, Journal of Clinical Oncology 2009
Tumors suitable for resection at
presentation
Tumors suitable for biopsy only at
presentation

Image defined risk factors in neuroblastic tumors
Neck:
• Tumor encasing carotid and/or vertebral artery and/or internal jugular vein
• Tumor extending to base of skull
• Tumor compressing the trachea
Cervico - thoracic junction:
• Tumor encasing brachial plexus roots
• Tumor encasing subclavian vessels and/or vertebral and/or carotid artery
• Tumor compressing the trachea
Thorax:
• Tumor encasing the aorta and/or major branches
• Tumor compressing the trachea and/or principal bronchi
• Lower mediastinal tumor, infi ltrating the costo - vertebral junction between
T9 and T12
Thoraco - abdominal:
• Tumor encasing the aorta and/or vena cava

Image defined risk factors in neuroblastic tumors
Abdomen/pelvis:
• Tumor infiltrating the porta hepatis and/or the hepatoduodenal ligament
• Tumor encasing branches of the superior mesenteric artery at the mesenteric root
• Tumor encasing the origin of the coeliac axis, and/or of the superior mesenteric artery
• Tumor invading one or both renal pedicles
• Tumor encasing the aorta and/or vena cava
• Tumor encasing the iliac vessels
• Pelvic tumor crossing the sciatic notch
Intraspinal tumor extension whatever the location provided that:
• More than one third of the spinal canal in the axial plane is invaded
and/or
• the perimedullary leptomeningeal spaces are not visible and/or
• the spinal cord signal is abnormal Infiltration of adjacent
organs/structures:
• Pericardium, diaphragm, kidney, liver, duodeno - pancreatic block, and
mesentery

The COG has been collecting and evaluating INRGSS data since 2006.
A COG trial that opened in 2014 uses the INRGSS along with input from
the surgeon to determine therapy for subsets of patients not at high
risk, including those with L1, L2, and MS disease (ANBL1232
[NCT02176967]).

01 02 03
Age
01
Disease stage
02
1. Tumor Histology
2. Tumor Genomic Features
Tumor biologic features
03

1. Histology
Shimada, H et al. The International Neuroblastoma Pathology Classification (the Shimada system).
Cancer 1999, 86, 364–372.
• The International Neuroblastoma Pathology Classification System
(INPC) relates histopathologic features to clinical outcome and is used
for risk classification.
• Tumors are categorized as favorable or unfavorable histologic subtype
based upon the degree of
 Neuroblast differentiation,
 Schwannian stroma content,
 Mitosis-karyorrhexis index (MKI), and
 Age at diagnosis.

• Amplification of the MYCN gene
• Tumor cell ploidy (DNA index)
• Loss of heterozygosity (LOH) of 1p or 11q

Current risk classification doesn't utilize
• Aberrations of ALK (ch2p23)
• 17q gain
• ATRX (alpha thalassemia/mental retardation syndrome X linked) and
• TERT (telomerase reverse transcriptase)
• AT-rich interactive domain 1A and B (ARID1a/1b) deletions
and point mutations

Current risk classification doesn't utilize
There are additional genomic features that may be useful particularly in the non-
high-risk NB group to distinguish patients with a more favorable outcome from
those who do not fare as well.
• Ha-ras p21 gene expression,
• Positive TrkA and low affinity nerve growth factor receptor mRNA expression,
• Parental imprinted miRNA (maternal miR-487b and paternal miR-516a-5p) expression,
• Four genes (DUSP12, DDX4, IL31RA and HSD17B12) associated with low risk disease.
Gattolliat, C.H et al. Expression of two parental imprinted miRNAs improves the risk stratification of
neuroblastoma patients. Cancer Med. 2014, 3, 998–1009.

Somatic
Whole chromosomal gains (NCAs), lack of structural changes and hyperdipolid DNA content
• Segmental chromosomal aberrations (SCAs) and diploid DNA content
• Somatic genetic mutations (rare)
• Familial NB
• Neurofibromatosis
• Beckwith-wiedmann
• Li-fraumeni
• Noonan’s
Germline
Molecular pathogensis

 Tumor cell ploidy:
 Hperdiploidy = (DNA index [DI] >1).
 Can be measured by flow cytometry.
 Value:
1. It is associated with lower stage.
2. It is associated with better prognosis.
3. It′s effect lost in children >2 years.
Gain of genetic materialSomatic
Near-diploid (and near-tetraploid) tumors tend to
behave more aggressively.

 MYCN oncogene amplification (ch2p24)
 Aberrations of ALK (ch2p23)
– Amplification detected in 2-3% of NB tumors
– Activating aberrations in 8-10% of NB
 17q gain (specific gene not known)
– detected in >60% of tumors

 Chromosome 1p36
– detected in 23-30% of tumors & associated with MYCNA
– It is associated with a poor prognosis.
– LOH of 1p was predictive of local recurrences in low stage disease.
 Chromosome 11q23
– detected in 30 - 40% of tumors & not associated with MYCNA
– It is correlated with ↑ incidence of relapse particularly metastatic relapses.
 Chromosome 14q32
– detected in 20 - 25%
Loss of genetic materialSomatic
Others: ch 3p, 4p, 5q, 18q

Frequency of detection the genetic
alterations chromsome 1p
deletion, chromosome 11q deletion
and chromosome 17q gain among
397 patients without MYCN
amplification harbouring at least
one genetic alteration in the INRG
database.
Schleiermacher G et al. Segmental chromosomal alterations have prognostic impact in neuroblastoma: a report from the INRG project.
British Journal of Cancer (2012) 107, 1418–1422 & 2012 Cancer Research UK All rights reserved 0007 – 0920/120

Schleiermacher G et al. Segmental chromosomal alterations have prognostic impact in neuroblastoma: a report from the INRG project.
British Journal of Cancer (2012) 107, 1418–1422 & 2012 Cancer Research UK All rights reserved 0007 – 0920/120
Event-free and overall survival in 505 patients without MYCN amplification for whom a genomic type could
be attributed. ‘Segmental’ genomic type: presence of either chromosome 1p deletion and/or chromosome
11q deletion and/or chromosome 17q gain. No segmental changes: no alteration for all three genetic
markers.

Holly J. Meany et alSignificance of Clinical and Biologic Features in Stage 3 Neuroblastoma: A Report from the International
Neuroblastoma Risk Group Project. DOI 10.1002/pbc.25134 Published online 7 July 2014 in Wiley Online Library
Patients with INSS Stage 3, MYCN-non-amplified neuroblastoma. EFS and OS in patients <547
days of age stratified by 11q no aberration (n¼78) versus 11q aberration (n¼11).

 ATRX (alpha thalassemia/mental retardation syndrome X linked)
and TERT (telomerase reverse transcriptase)
– ATRX detected in older NB patients
– Tumors grow more slowly & harder to cure
- To elongate telomeres, which is a known mechanism of survival in cancer cells.
- AT-rich interactive domain 1A and B (ARID1a/1b)
deletions and point mutations
– chromatin remodeling proteins
Somatic genetic mutationsSomatic (Rare)
Others: p53 & PTPN11

Somatic genetic mutationsSomatic (Rare)

Receptor tyrosine kinases
Growth factors
A splicing variant of TrkA, to which NGF
does not ligate, is found dominantly in
unfavorable neuroblastomas.
Elevated TrkA expression is correlated with
favorable biological features including
 Younger age at diagnosis,
 Lower stage and
 Absence of MYCN amplification.
Highly expressed in MYCN-amplified
Associated with a poor prognosis

Differences in Genomic Profiles and Outcomes
between Thoracic and Adrenal
Neuroblastoma?

Sum up
Adverse impact on prognosis

01
Age
Histology
DNA IN-MYC
Response
NB
Prognostic Factors

Sum up
Adverse
impact on
prognosis

Advances in Treatment Strategies for
Non high risk Neuroblastoma
LR IR

Low Risk
Advances in Treatment Strategies

Advances in Treatment Strategies for Low risk NB
SIOPEN
LNESG1
COG
P9641
Surgery alone
for localize
tumors?
1998→ 2004
5-y OS 97%
5-y OS (stage I) 98%
5-y OS (stage II) 93%
915 Patients
Study Group Time & patients N OS EFS
1995→ 1999
401 Patients
Surgery alone
for localize
tumors?
5-y EFS 89% 5-y EFS (stage I) 94%
5-y EFS (stage II) 82%
Age Range 0- 20 y0- 20 y

• Importantly the EFS and OS rates for patients treated with surgery alone and for
patients treated with surgery and chemotherapy were not significantly different nor
were the rates of progressive disease or disease recurrence.
Douglas R et al. Outcome After Surgery Alone or With Restricted Use of Chemotherapy for Patients With Low-Risk Neuroblastoma: Results of Children’s
Oncology Group Study P9641. Published Ahead of Print on April 23, 2012 as 10.1200/JCO.2011.37.9990
Similar results were seen on an International Society of Pediatric Oncology European
Neuroblastoma (SIOPEN) study in patients with MYCN non-amplified localized neuroblastoma
(LNESG1).

GPOH
NB95-s and
97
COG
ANBL00P2
Observation
alone?
2001→ 2010
3-y OS 100%
5-y OS 99%
87 Patients
1995→ 2004
93 Patients
Observation
alone of
unresected
tumors ?
3-y EFS 97.7% 5-y EFS 56%
Age Range < 1 y0- 6 Months

Treatment - low risk NB
R• In recent years, clinical trials for infants with localized adrenal masses have
demonstrated excellent outcomes with observation alone.
• These masses tend to spontaneously regress, and can be observed without
surgical resection or chemotherapy.
• In a COG prospective study for perinatal NB (ANBL00P2) observing infants less
than 6-months old with small adrenal masses without biopsy,
 81% of subjects were effectively managed with expectant observation alone,
 while the remaining 19% eventually underwent resection.
 None required chemotherapy.
 3-year EFS rates were 97% with OS rates of 100%.
Nuchtern JG, London WB, Barnewolt CE, et al. A prospective study of expectant observation as primary therapy for
neuroblastoma in young infants: a Children’s Oncology Group study. Ann Surgery. 2012;256:573–580.
(<16 mL in volume if solid and <65 mL in
volume if ≥25% cystic)

Treatment - low risk NB
R• This strategy has become standard of practice, and the active COG ANBL1232
study (NCT02176967) has extended the age of observation for a subset of
localized tumors up to 12 months to determine whether observation alone is
appropriate in this age group as well.
• Infants with stage 4S/MS neuroblastoma may demonstrate spontaneous
regression, likely due to the unique biological features of neuroblastoma in
infants, including
 Near-triploid DNA content and
 Increases in expression of genes from the chromosome 1p36 region.
Lavarino C, Cheung N-K, Garcia I, et al. Specific gene expression profiles and chromosomal abnormalities are associated with
infant disseminated neuroblastoma. BMC Cancer. 2009;9:44.

Low Risk Neuroblastoma:
1. Observation without biopsy
2. Surgery followed by observation
3. Chemotherapy with or without surgery
4. Radiation therapy
EFS
OS
> 90%
> 90%

Asymptomatic stage
4S disease
Some infants with localized NB
Some newborns with small
adrenal masses
Observe in LR NB1
{Nuchtern et al., 2012}

Observation without biopsy
Treatment
• Small stage I or stage II adrenal masses
• Infants younger than 6 months
• Asymptomatic
Observation
• Serial ultrasound measurement of the lesion and
• Measurement of urine VMA/HVA
• An increase in the size of the lesion or urine VMA/HVA should prompt surgical resection.
• For young infants/neonates, formal staging investigations (e.g. bone marrow aspirates, mIBG
scintigraphy) may be deferred until the age of 3 months provided there is no increase in lesion size or
urine VMA/HVA levels

Chemotherapy
Surgery
Treat 2
• Surgery alone is the primary treatment for low-risk
tumors. {De Bernardi et al., 2008}
• It should be delayed when <50 % of the tumor can
be safely removed and neoadjuvant chemotherapy
should be administered prior to surgery.
• Organ sparing goal (complete resection not
mandatory)

• Vascular injury: injury of major vessels including aorta, vena cava and renal and mesenteric
vessels, which usually result in a serious operative mortality.
• Renal loss: tumor invasion, arterial damage and renal vein thrombosis result in total nephrectomy.
• Chylous acites or chylothrax: lymphatic leakage during surgery frequently results in
postoperative chylous ascites or chylothrax. This revolves usually within several weeks or months but
usually results in delayed subsequent adjuvant chemotherapy. Management is usually at first
conservative. To decease lymphatic flow, fasting with total parental nutrition is required. In failure,
surgical repair is adopted, including direct ligation, fibrin glue application or peritoneo-venous shunt.
• Postoperative diarrhea: diarrhea is considered to result from the damage to inhibit
sympathetic nervous supply when dissected celiac and supramesenteric artery.
• Horner’s syndrome of the apical NB.
• Adhesive bowel obstruction.
• Neural injury: intra-spinal hematoma, its cord compression or direct cord injury, resulting in
pelvic nerve palsy, fecal incontinence, neurogenic bladder, and/or erectile dysfunction.
Complications of surgery

Role of laparoscopic
surgery ?

Role of laparoscopic surgery
Conclusion:
• IDRF-negative might be a good indication for laparoscopic total
resection of abdominal neuroblastoma.
• However, deformation or subtotal encasement of major vessels,
especially of the vena cava, should also be considered as IDRF-positive
for Minimally invasive surgery.

Contraindications of laparoscopic surgery
 Absolute contraindications in pediatric surgical oncology include:
a. Associated coagulation disorder,
b. Respiratory compromise of any etiology, and
c. An infective focus, especially in the anterior abdominal wall, especially in the periumbilical
region.
 Relative contraindications include:
a. Extensive previous surgery that has resulted in dense intra-abdominal/ thoracic adhesions
and
b. Ablative MIS when tumor is very huge as it may lead to tumor spillage with its sequelae.

Chemotherapy
Surgery
Treat 2
• Surgery alone is the primary treatment for low-risk
tumors. {De Bernardi et al., 2008}
• It should be delayed when <50 % of the tumor can
be safely removed and neoadjuvant chemotherapy
should be administered prior to surgery.
• Organ sparing goal (complete resection not
mandatory)
• low or moderate intensity;
Those whose tumors cannot be resected
Who have threatening symptoms of
spinal cord compression or respiratory or
bowel compromise or liver dysfunction.

Life threatening symptoms
• Intraspinal neuroblastoma
Patients who either have symptoms of spinal cord
compression or have a spinal tumour component
that occupies more than one third of the spinal
canal on the axial plane and/or the perimedullary
leptomeningeal spaces are not visible and/or the
spinal cord signal is abnormal.
• Pain requiring opiate treatment
• Gastrointestinal
- Vomiting needing nasogastric/IV support
- Weight loss >10% body weight
• Respiratory: Respiratory distress without evidence of infection
 Tachypnoea >60
 Oxygen need
 Ventilatory support
• Cardiovascular System
- Hypertension
- IVC compression +/- leg oedema
• Renal
- Impaired renal function, creatinine increased x2 ULN
- Poor urine output, less than 2mL/kg/hour
- Hydroureter/hydronephrosis
• Hepatic
- Abnormal liver function >2 ULN
- Evidence of DIC
- Platelets <50 x 109/L
• Bladder/Bowel dysfunction secondary to a mass
effect.
• A very large tumor volume causing concern of
possible tumor rupture and/or the possible rapid
development of systemic upset.
CHILDREN’S CANCER AND LEUKAEMIA GROUP (CCLG) NEUROBLASTOMA SPECIAL INTEREST GROUP
JANUARY 2015
A scoring system evaluating the symptoms of clinical deterioration is being
prospectively evaluated in a current COG study (NCT02176967).

Treatment Options Under
Clinical Evaluation
a. Genomic features include
 MYCN gene amplification,
 Segmental chromosome aberrations (somatic
copy number loss at 1p, 3p, 4p, or 11q, or
somatic copy number gain at 1p, 2p, or 17q),
and
 DNA index.
b. Favorable genomic features are defined by
 one or more whole-chromosome gains or
 hyperdiploid tumor (DNA index >1) in the
absence of segmental chromosome
aberrations as defined above.
An ongoing trial (ANBL1232)

CCLG
NCAL2
Over 600 members, working in a network of 21 Pediatric Oncology Centers
throughout the United Kingdom and Ireland, and including over 70
corresponding members from other countries around the world.
* Consider surgery if image defined risk factors become negative
No LTS
NCA LTS
SCA No LTS
LTSSCA
Observe
2 Carbo/vp16
LTS resolve *Observe
LTS persist *2 CADO #
# No indication for further chemotherapy
4 Carbo/vp16
2 Carbo/vp16
LTS resolve *2 Carbo/vp16
LTS persist *2 CADO #

NCAMs
* Surgical resection of primary tumor not indicated in this group
No LTS
NCA LTS
SCA No LTS
LTSSCA
Observe
2 Carbo/vp16
LTS resolve *Observe
LTS persist 2 CADO*
# Proceed with a surgical resection of the primary tumor if IDRF negative
4 Carbo/vp16#
2 Carbo/vp16
LTS resolve 2 Carbo/vp16#
LTS persist 2 CADO #

Accepted on October 5, 2018 and published at jco.org on November 16, 2018: DOI https://doi.
org/10.1200/JCO.18. 00419 Clinical trial information: NCT00499616.
(ANBL0531 trial)

(ANBL0531 trial)
 Successful completion of therapy was defined as
• Completion of assigned chemotherapy,
• Resolution of symptoms,
• Achievement of ≥ 50% reduction in primary tumor volume, and
• Elimination of bone marrow and skin metastases.
 Liver metastases were not used in evaluation of response because of
the known difficulty in interpreting imaging.
 Patients could receive up to eight cycles of chemotherapy as needed to
meet the criteria for completion of therapy.

(ANBL0531 trial)
ANBL0531 4S eligible
ANBL00B1 low-risk asymptomatic
patients with 4S disease

Intermediate Risk
Low Risk
Advances in Treatment Strategies

Advances in Treatment Strategies for intermediate risk NB
SIOPEN
99
COG
A3961
Treatment
reduction
based on risk ?
1997→ 2005
3-y OS 96%
479 Patients
Treatment
reduction
based on risk ?
3-y EFS 88%
Age Range < 1 y vs > 1y0- 21 y

> 90%
> 85%
EFS
OSIntermediate Risk Neuroblastoma:
•Surgery
•Chemotherapy
 Moderately intensive multi agents chemotherapy
 The COG A3961 study subdivided patients with IR NB into those with:
• Favorable biology (having both favorable histology and a DNA index
of more than 1) [ 4 cycles of chemotherapy]
• Unfavorable biology (having unfavorable histology, a DNA index of 1
or less, or both) [ 8 cycles of chemotherapy]

David L. Baker et al. Outcome after Reduced Chemotherapy for Intermediate-Risk Neuroblastoma. n engl j med
88%
96%
1 2 3 4 Learned lessons

1 2 3 4 Learned lessons

363;14 nejm.org september 30, 2010.

> 90%
> 85%
EFS
OSIntermediate Risk Neuroblastoma:
•Surgery
•Chemotherapy
• Upfront biopsy for genetic and histology data
• Delayed resection to achieve ≥50% reduction primary tumor size;
• Complete resection NOT mandatory
• The ultimate extent of surgical resection necessary for optimal
outcomes has not yet been determined. {Baker et al., 2010}

SIOPEN 99.1 SIOPEN 99.2 SIOPEN 99.2
• Study time 1999→ 2004 1999→ 2004 2001→ 2006
• N. patients 120 170 160
• Age range < 1 y < 1 y > 1 y
• Stage Localized unresected Disseminated Localized unresected
• MYCN Non amplified
• 5-OS 99 96 87
• 5-EFS 90 88 76
Treatment reduction based on risk ?